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US9687460B2 - Autoimmune-induced glutamatergic receptor dysfunction methods and treatments - Google Patents

Autoimmune-induced glutamatergic receptor dysfunction methods and treatments Download PDF

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US9687460B2
US9687460B2 US14/893,992 US201414893992A US9687460B2 US 9687460 B2 US9687460 B2 US 9687460B2 US 201414893992 A US201414893992 A US 201414893992A US 9687460 B2 US9687460 B2 US 9687460B2
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cancer
encephalitis
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Uriel Heresco-Levy
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SARAH HERZOG MEMORIAL HOSPITAL-EZRATH NASHIM
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to pharmaceutical compositions for the treatment of autoimmune-induced glutamatergic receptor dysfunction and disorders related to same. More particularly, the present invention relates to the use of N-methyl-D-aspartate type glutamate receptor (NMDAR) agonists (NMDAR agonists, also known as NMDA agonists) and partial agonists for the treatment of autoimmune-induced glutamatergic receptor encephalitis.
  • NMDAR N-methyl-D-aspartate type glutamate receptor
  • NMDAR are a type of receptor for the excitatory neurotransmitter glutamate.
  • NMDAR contain additional modulatory sites, including the following: glycine binding site, polyamine binding site, redox site, Zinc (Zn) site, phosphorylation sites, post-synaptic membrane docking sites and protein-protein interaction sites.
  • the glycine binding site is sensitive to monocarboxyllic amino acids including the endogenous amino acids glycineD-serine and D-alanine.
  • Glycine is synthesized via serine or threonine by serine hydroxymethyltransferase.
  • Synaptic glycine concentrations are regulated by type 1 (GLYT1) and type 2 (GLYT2) glycine transporters, as well as by other amino acid transporters belonging to Systems A, L, ASC, and N.
  • GLYT1 transport inhibitors such as N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy) propyl] sarcosine (NFPS), potentiate NMDAR activity in vivo, suggesting a critical role for glycine transporters in NMDAR regulation.
  • Methylated glycine derivates e.g., methylglycine, sarcosine
  • D-serine and D-alanine are metabolized by D-amino acid oxidase (DAAO), which is localized particularly in hindbrain.
  • DAAO D-amino acid oxidase
  • G72 novel protein termed G72, which may affect metabolic activity of the DAAO enzyme.
  • Glycine, D-serine and D-alanine levels in brain may be modulated by administering exogenous compound (i.e., glycine, D-serine or D-alanine), or naturally occurring precursors to these compounds including but not limited to L-serine, L-phosphoserine, D-phosphoserine and threonine, or by modulation of the synthetic enzymes serine hydroxymethyltransferase or serine racemase.
  • D-Serine or D-alanine levels may also be increased by modulation inhibiting D-serine or D-alanine breakdown, for example, by antagonizing DAAO activity either directly or indirectly (e.g., via modulatory proteins).
  • Limbic encephalitis refers to an inflammatory process that predominantly affects the grey matter of the medial temporal lobes, amygdala and orbito-frontal cortex and produces cognitive impairment along with emotional and behavioral disturbances, sleep disruption, seizures and sometimes dementia.
  • autoimmune LE was mostly viewed as a paraneoplastic disorder associated with onconeural antibodies to intracellular antigens, cytotoxic T-cell mediated pathogenesis and limited response to treatment.
  • accumulating data suggest that the clinical and immunological spectra of LE are far more extensive than initially considered.
  • autoimmune encephalitides characterized by antibodies against neuronal cell surface antigens, less frequent association with cancer, an antibody-mediated pathogenesis and improved treatment response following immunotherapy.
  • Receptors and proteins that are critically involved in glutamatergic neurotransmission and synaptic plasticity, including N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptors (NMDAR, AMPAR) are cardinal target antigens in many of these disorders.
  • the antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble the pharmacological or genetic models in which the antigen is disrupted.
  • glutamatergic neurotransmission in a variety of psychiatric disorders, including schizophrenia and affective disorders, the identification of specific autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders and to provide additional guidance for psychiatric diagnostics and treatments development.
  • AGRD autoimmune-induced glutamatergic receptor dysfunctions
  • NMDAR play a key role in the regulation of movement and striatal function and in the modulation of executive functions and effect.
  • NMDARs are found on multiple classes of neuron within striatum including projection neurons and internuerons.
  • NMDARs are composed of multiple subunits including an NR1 subunit which is present in virtually all functional NMDARs, and NR2 subunits that are present in variable proportions.
  • NR2A-D Four NR2 subunits (NR2A-D) have been described.
  • NR2A expression is high in GABAergic neurons that express the marker GAD67, intermediate over SP neurons, low in ENK neurons, not found in cholinergic and SOM neurons.
  • NR2B expression is intense in all populations of neurons, while expression of NR2C,D is weak
  • NMDARs controlling GABA and DA release are less sensitive to NMDA than receptors controlling spermidine or ACh release.
  • Anti-NMDAR encephalitis is an autoimmune encephalitis characterized by the presence of antibodies against synaptic NMDAR. Anti-NMDAR encephalitis has become the most common and best characterized antibody-defined autoimmune neuronal disorder. Nevertheless, additional AGRD syndromes, associated with the presence of antibodies against diverse GLU neurotransmission-related antigens, including different NMDAR subunits, AMPAR and metabotropic receptor proteins are being increasingly characterized. Furthermore, the presence of NMDAR and AMPAR directed antibodies in conjunction with antibodies to different other types of receptors and neurotransmission systems has been reported. Overall, in view of the impact and interest generated by these findings, it is likely that during the next decade we will witness a significant expansion in the identification, characterization and understanding of AGRD.
  • the encephalitis associated with antibodies against NMDAR predominantly affects children and young adults, occurs with or without tumor association, responds to treatment but can relapse.
  • the presence of a tumor (usually an ovarian teratoma) is dependent on age, sex and ethnicity, being more frequent in women older than 18 years and black women.
  • anti-NMDAR encephalitis The exact incidence of anti-NMDAR encephalitis is unknown but it seems to be more frequent than any other known paraneoplastic encephalitis. Furthermore, due to the rareness of the syndrome and the varied clinical presentations ranging from psychiatric and neurological manifestations to autonomic dysregulation, the anti-NMDAR syndrome is still misdiagnosed and under-recognized.
  • Serum and CSF of patients suspected with the syndrome should be checked for reactivity with the hippocampal tissue on rat brain sections, cell-surface labeling of cultured hippocampal neurons, or reactivity with NR1/NR2 transfected human embryonic kidney (HEK) cells.
  • the CSF may also present pleocytosis, increased protein concentration, oligoclonal bands and high IgG index.
  • Electroencephalogram can frequently demonstrate focal or diffuse slow activity during episodes of dyskinesias or abnormal movements and less commonly it may show epileptic activity.
  • MRI shows small areas of Fluid Attenuated Inversion Recovery (FLAIR) abnormalities in cerebral cortex outside the medial temporal lobes, sometimes involving the cerebellum and brainstem or transient enhancement of overlying meninges.
  • FLAIR Fluid Attenuated Inversion Recovery
  • Immunotherapy and the detection and removal of a tumor are the most important components in the treatment of anti-NMDAR encephalitis.
  • Rosenfeld and Dalmau have proposed a structured treatment approach to patients with synaptic autoimmunities such as anti-NMDAR encephalitis.
  • cyclophosphamide monthly and rituximab (weekly for 4 weeks starting with the first dose of cyclophosphamide) should be initiated.
  • other forms of immunosuppression should be considered.
  • immunosuppression with mycophenolate mofetil or azathioprine for at least one year after initial treatments should be considered, to reduce the high rate of relapses after recovery.
  • ECT neuroleptic administration actually exacerbating neuropsychiatric symptoms and movement abnormalities.
  • ECT has been used for targeting catatonic presentations in patients with autoimmune encephalitis, including anti-NMDAR encephalitis.
  • Agitated aggression has been treated with various conventional and atypical antipsychotics with limited treatment response.
  • Atypical antipsychotics have also been used to target psychotic symptoms without significant success and have the potential to worsen dyskinesia and other movement abnormalities.
  • NMDAR agonist treatment significantly improves quality of life in subjects suffering from encephalitis associated with antibodies against NMDAR or other diseases whose pathogenesis is associated with the presence of antibodies against NMDAR, including reducing psychopathology symptoms, improving motor symptomatology and improving cognitive performance, including improving working memory, abstraction and mental flexibility.
  • This invention provides a method for enhancing NMDAR-mediated neurotransmission for encephalitis associated with antibodies against NMDAR or other diseases whose pathogenesis is associated with the presence of antibodies against NMDAR.
  • the invention contemplates use of glycine (GLY), D-Serine (DSR) or D-cycloserine (DCS), or combinations thereof, for their agonist activity for the NMDAR-associated GLY site in connection therewith.
  • the invention contemplates use of GLY transport inhibitors and D-amino acid oxidase inhibitors in connection therewith.
  • the invention contemplates use of alanine-serine-cysteine transporter (ASCT) inhibitors and in some embodiments, the invention contemplates use of D-serine transporter inhibitors in connection therewith.
  • ASCT alanine-serine-cysteine transporter
  • the present invention also provides for the use of an NMDAR agonist or partial agonist in the manufacture of a pharmaceutical composition, medical food, or dietary supplement for the treatment of encephalitis associated with antibodies against NMDAR or other diseases whose pathogenesis is associated with the presence of antibodies against NMDAR.
  • FIG. 1A and FIG. 1B demonstrate the reduction of an extreme delta brush (EDB) pattern after six weeks of D-Serine (DSR) therapy in a patient positive for the presence of anti-NR1 NMDAR antibodies. Pre- and Post-treatment effects are shown, as designated. Electroencephalogram (EEG) results with eyes opened are shown in FIG. 1A . Normal EEG background activity with superimposed semi-rhythmic diffuse delta frequency bursts more predominantly over the right frontal-temporal areas, characteristic of EDB is seen prior to treatment, that is significantly reduced post treatment.
  • FIG. 1A Electroencephalogram
  • FIG. 2A and FIG. 2B show electroencephalogram (EEG) coherence values pre- and post-six weeks of D-serine administration in the same patient, respectively.
  • Light gray lines indicate the amount of coherence between electrodes. Distinct new patterns of EEG coherence are present following DSR treatment, across all frequency bands.
  • This invention provides a method of enhancing NMDAR-mediated neurotransmission in a disease associated with NMDAR antibody production, said method comprising administering an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor, a partial agonist such as D-cycloserine or a combination thereof to said subject.
  • This invention also provides a method of mitigating the severity of, mitigating the pathogenesis of, lowering the incidence of and/or treating a disease associated with NMDAR antibody production, said method comprising administering an agent, which is an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor, D-cycloserine or a combination thereof to said subject.
  • an agent which is an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor, D-cycloserine or a combination thereof to said subject.
  • the disease associated with NMDAR antibody production is paraneoplastic autoimmune encephalitis. In some embodiments, the disease associated with NMDAR antibody production is non-paraneoplastic autoimmune encephalitis. In some embodiments, the disease associated with NMDAR antibody production is anti-NMDAR encephalitis.
  • the methods include identification of a subject with a disease associated with NMDAR antibody production. In some embodiments, according to this aspect, such methods include assessing qualitative or quantitative levels of NMDAR antibodies in a biological sample from a suspected subject.
  • the biological sample used in the methods described herein is a body fluid that is, in another embodiment, a cerebro-spinal fluid (CSF). In another embodiment, the body fluid is plasma. In another embodiment, the body fluid is any other type of fluid known in the art. Each possibility represents a separate embodiment of the present invention.
  • the biological sample is amniotic fluids, blood, sera, saliva, or their combination in another embodiment.
  • the methods include identification of a subject with a disease associated with NMDAR antibody production by assessing other neurologic or psychiatric symptomatology.
  • encephalitis causes deficits that are characteristically dominated by rapid and severe loss of short-term memory.
  • patients show encephalitis with evidence of cancer.
  • the encephalitis is associated with seizures. In another embodiment, the encephalitis is associated with a diencephalic syndrome. In another embodiment, the encephalitis is associated with a psychiatric symptom. In another embodiment, the encephalitis is associated with an abnormality in cognition. In another embodiment, the encephalitis is associated with an abnormality in behavior. In another embodiment, the encephalitis is associated with amnesia. In another embodiment, the encephalitis is associated with a memory deficit. In another embodiment, the encephalitis is associated with memory problems. In another embodiment, the encephalitis is associated with a hypokinetic syndrome.
  • the encephalitis is associated with a movement disorder. In another embodiment, the encephalitis is associated with abnormal movements. In another embodiment, the movement disorder is Stiff Man/Person Syndrome. In another embodiment, the movement disorder is any other movement disorder known in the art. Each possibility represents a separate embodiment of the present invention.
  • the encephalitis is associated with a decreased level of consciousness. In another embodiment, the encephalitis is associated with hypoventilation.
  • the encephalitis is associated with, dysfunction of any part of the brain or spinal cord. In another embodiment, the encephalitis is associated with a combination of any of the above symptoms or disorders.
  • the encephalitis is associated with a tumor.
  • the tumor is an ovarian teratoma.
  • the tumor is a thymic tumor.
  • the tumor is a testicular tumor.
  • the cancer associated with the encephalitis is a cervical cancer tumor.
  • the cancer is a head and neck cancer tumor.
  • the cancer is a breast cancer tumor.
  • the cancer is an ano-genital cancer tumor.
  • the cancer is a melanoma.
  • the cancer is a sarcoma.
  • the cancer is a carcinoma.
  • the cancer is a lymphoma.
  • the cancer is a leukemia. In another embodiment, the cancer is mesothelioma. In another embodiment, the cancer is a glioma. In another embodiment, the cancer is a germ cell tumor. In another embodiment, the cancer is a choriocarcinoma.
  • the cancer is pancreatic cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is gastric cancer. In another embodiment, the cancer is a carcinomatous lesion of the pancreas. In another embodiment, the cancer is pulmonary adenocarcinoma. In another embodiment, the cancer is colorectal adenocarcinoma. In another embodiment, the cancer is pulmonary squamous adenocarcinoma. In another embodiment, the cancer is gastric adenocarcinoma. In another embodiment, the cancer is an ovarian surface epithelial neoplasm (e.g. a benign, proliferative or malignant variety thereof). In another embodiment, the cancer is an oral squamous cell carcinoma.
  • the cancer is an oral squamous cell carcinoma.
  • the cancer is nonsmall-cell lung carcinoma. In another embodiment, the cancer is an endometrial carcinoma. In another embodiment, the cancer is a bladder cancer. In another embodiment, the cancer is a head and neck cancer. In another embodiment, the cancer is a prostate carcinoma.
  • the cancer is an acute myelogenous leukemia (AML). In another embodiment, the cancer is a myelodysplastic syndrome (MDS). In another embodiment, the cancer is a non-small cell lung cancer (NSCLC). In another embodiment, the cancer is a Wilms' tumor. In another embodiment, the cancer is a leukemia. In another embodiment, the cancer is a lymphoma. In another embodiment, the cancer is a desmoplastic small round cell tumor. In another embodiment, the cancer is a mesothelioma (e.g. malignant mesothelioma). In another embodiment, the cancer is a gastric cancer. In another embodiment, the cancer is a colon cancer. In another embodiment, the cancer is a lung cancer.
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • NSCLC non-small cell lung cancer
  • the cancer is a Wilms' tumor.
  • the cancer is a leukemia.
  • the cancer is a lymph
  • the cancer is a breast cancer. In another embodiment, the cancer is a germ cell tumor. In another embodiment, the cancer is an ovarian cancer. In another embodiment, the cancer is a uterine cancer. In another embodiment, the cancer is a thyroid cancer. In another embodiment, the cancer is a hepatocellular carcinoma. In another embodiment, the cancer is a thyroid cancer. In another embodiment, the cancer is a liver cancer. In another embodiment, the cancer is a renal cancer. In another embodiment, the cancer is a kaposis. In another embodiment, the cancer is a sarcoma. In another embodiment, the cancer is another carcinoma or sarcoma.
  • the tumor is any other type of tumor known in the art.
  • encephalitis diseases in the art.
  • patients with encephalitis develop subacute confusion, irritability, depression, sleep disturbances, seizures, short-term memory loss, and/or dementia.
  • the pathological substrate of encephalitis is an inflammatory disorder that involves the limbic system (hippocampi, amygdala, and cingulate gyms).
  • biopsy and autopsy studies demonstrate interstitial and perivascular infiltrates of T cells, and less frequently B cells, along with microglial activation, neuronal degeneration, and/or gliosis.
  • inflammatory infiltrates are found in areas distant from the limbic system.
  • the infiltrates remain mild and clinically silent. In another embodiment, the infiltrates become prominent and develop into a disorder called encephalomyelitis. Additional methods of diagnosing encephalitis are described, for example, in Gultekin S H et al (Brain 2000; 123:1481-1494). Each possibility represents a separate embodiment of the present invention.
  • the method further comprises the step of removing the tumor, providing immunotherapy or a combination thereof.
  • Agents may be screened for effectiveness in stimulating NMDA transmission in vitro using assays, for example, measuring modulation of NMDAR-mediated activity in hippocampal slices or of NMDAR-stimulated dopamine release in isolated mouse striatum.
  • Agents may be screened in vivo using assays, for example, measuring amphetamine induced dopamine release or NMDAR-mediated electrophysiological activity. Agents will be effective in ameliorating movement disorders at doses sufficient to potentiate NMDAR-mediated neurotransmission in vivo.
  • prodrugs may also be administered.
  • Prodrugs are defined as agents that are not themselves agonists of the NMDAR, but which enter the brain and are converted or metabolized there into effective agonists.
  • An example of a glycine prodrug is milacemide.
  • Simple precursors can be made by esterification, alkylation or other linkage, most effectively to hydrophobic groups that increase lipophilicity and diffusion into CNS.
  • NMDAR agonists including but not limited to glycine, D-serine, or D-alanine
  • glycine, D-serine, or D-alanine are conjugated to molecules that are actively transported into the CNS, leading to increased central penetration.
  • Precursors to glycine, D-serine or D-alanine, including threonine, L-phosphoserine and D-phosphoserine may also be incorporated into prodrugs.
  • the methods of the invention are useful in confirming suspected encephalitis associated with antibodies against NMDAR or other diseases whose pathogenesis is associated with the presence of antibodies against NMDAR, which method comprises confirming said encephalitis associated with antibodies against NMDAR or other diseases whose pathogenesis is associated with the presence of antibodies against NMDAR, as a result of a positive response by any of the indicia herein described, to treatment with an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor, a partial agonist such as D-cycloserine or a combination thereof.
  • compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.
  • suitable carriers or excipients such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.
  • Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • Tablet binders that may be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.
  • Liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents.
  • Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated.
  • Injectable compositions may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).
  • the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused.
  • Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients.
  • a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil.
  • a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution
  • depot forms of the compounds e.g., decanoate, palmitate, undecylenic, enanthate
  • the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like.
  • the term “comprise” or grammatical forms thereof refers to the inclusion of the indicated components of this invention, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry.
  • the term “about” refers to a variance of from 1-10%, or in another embodiment, 5-15%, or in another embodiment, up to 10%, or in another embodiment, up to 25% variance from the indicated values, except where context indicates that the variance should not result in a value exceeding 100%.
  • the present invention provides combined preparations.
  • a combined preparation defines especially a “kit of parts” in the sense that the combination partners as defined above can be used independently or in different combinations i.e., simultaneously, concurrently, separately or sequentially.
  • Anti-NMDAR encephalitis is diagnosed in a study subjects. Diagnosis is based on a determination of the presence of NR1 IgG antibodies in the serum/CSF of the subjects.
  • CSF cerebrospinal fluid
  • the patients will receive D-serine for 6 wks in addition to the clinically determined treatment.
  • Dosages of D-serine assessed will include staggered treatment regimens, including administration the first week of 1500 mg/d; and subsequent weeks, the subject will be administered a dosage of 4000 mg/d.
  • a 5 cc. blood sample was obtained from each participating patient for the assessment of the presence of anti-NMDAR antibodies. Blood samples were prior to eating and prior to the administration of any type of medication.
  • Detection of autoantibodies against extracellular epitopes of NMDAR was performed in each of the serum samples obtained using a previously described cell-based assay (Takano et al., 2011 Neurosci Res 71:294-302).
  • Patient serum samples were analyzed using cells expressing mutant NMDAR subunits by immunocytochemistry and on-cell Western analysis using live cells stably expressing mutant NMDAR.
  • the presence of anti-NMDAR antibodies was evaluated using both X200 and X10 dilutions of the serum samples.
  • GluR ⁇ 1(NR1, GluN1) subunits of NMDAR alone were expressed on the cell surface and direct evidence was obtained of the presence or absence of autoantibodies recognizing extracellular epitopes of GluR ⁇ 1 and the induction of internalization by autoantibodies in the serum of study patients.
  • the serum of one patient was strongly positive at both serum sample dilutions for the presence of both IgG and IgM classes of anti-NR1 NMDAR antibodies.
  • the patient was a 67 year old single female having a diagnosis of schizophrenia according to DSM-IV-R criteria (American Psychiatric Association, 2000 Diagnostic and Statistical Manual of Mental Disorders—(DSM-IV-TR), 4th edition. American Psychiatric Association Washington D.C. (Text Revision)).
  • DSM-IV-R American Psychiatric Association
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • DSR is anaturally occurring amino acid that acts in vivo as an obligatoryco-agonist at the glycine modulatory site associated with NMDAR. No significant adverse events have been observed with DSR at doses of ⁇ 4 g/day. Both acute and chronic administration of 1-2 g DSR in humans is known to result in ⁇ 100 times increases in DSR serum levels (Kantrowitz et al., 2010, Schizophr Res 121:125-30; Heresco-Levy et al., 2005, Biol Psychiatry 57:577-85).
  • the trial consisted of two periods, starting with a 2 week lead-in/stabilization period ( ⁇ 2-0) following which the patient was entered in the second period of the study which consisted of a 6 week (0-6), open-label, fixed dose therapy phase.
  • the patient received adjuvant treatment with DSR, whose dose was increased from 1500 mg/day (week 1) to 2000 mg/day (weeks 2 and 3) to 3000 mg/day (weeks 4 and 5) and to 4000 mg/day (week 6).
  • the doses of the ongoing medication received by the patient remained fixed throughout the study and no changes in medication were performed.
  • EEG electroencephalogram
  • MRI brain magnetic resonance imaging
  • the assessment procedures used in the study included clinical and neurocognitive examinations. Motor and psychiatric symptoms as well as side-effects were rated biweekly throughout the study. The following instruments were used: 1) Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987, Positive and Negative Syndrome Scale (PANSS) rating manual. San Rafael Calif.: Social and Behavioral Sciences Documents); 2) Quality of Life Scale (QLS) (Wilkinson et al., 2000, Self-report quality of life measure for people with schizophrenia: the SQLS. Br J Psychiatry 177:42-6); 3) Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976, ECDEU Assessment Manual for Psychopharmacology-Revised.
  • PANSS Positive and Negative Syndrome Scale
  • QLS Quality of Life Scale
  • AIMS Abnormal Involuntary Movement Scale
  • neurocognitive assessment battery (nine computerized and two paper/pencil tests) was employed that measures accuracy and speed of performance in major cognition domains, including attention/vigilance, planning, short-term and working memory, decision making, abstraction and mental flexibility. All the tests were formatted like games and puzzles, and were administered to the patient as part of the comprehensive neuropsychiatric assessment at baseline and the end of study.
  • the neurocognitive battery included the 1) Test of Attentional Vigilance (TOAV, (Forbes, 1998, Journal of Clinical Psychology 54:461-476; Greenberg, 1993, Journal of Child Psychology and Psychiatry 34: 1019-3)); 2) Tower of London (TOL, (Shallice, 1982, Specific impairments of planning. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 298:199-209); 3-4) Digit Span Test (DST, forward and backward (Wechsler 1997, The Wechsler adult intelligence scale-III.
  • TOAV Test of Attentional Vigilance
  • TOAV Test of Attentional Vigilance
  • TOL Tower of London
  • DST Digit Span Test
  • Wechsler 1997 The Wechsler adult intelligence scale-III.
  • the patient completed two paper/pencil tests: 10-11) part A and part B of the Trail-Making-Test (TMT, (Reitan, 1958, Percept. Mot Skills 8:271-76; Reitan, 1992 Trail Making Test: Manual for administration and scoring. Arlington, Ariz.: Reitan Neuropsychology Laboratory>> according to the guidelines presented by Spreen and Strauss (1998)). All neurocognitive testing was completed in a private and quiet setting to limit any distractions. The tests instructions were displayed and read to the patient by a Ph.D.-level trained researcher.
  • TTT Trail-Making-Test
  • EDB Extreme delta brush
  • DSR treatment was well tolerated throughout the study and no side effects were registered. As shown in Table 1, the quality of life of the patient improved considerably during treatment with DSR, resulting by the end of the treatment period in an ⁇ 3 times reduction in terms of reported symptoms and side effects.
  • motor symptomatology as measured by AIMS and SAS scores, was minimal at baseline improvements were registered also in this domain following DSR administration (Table 1).
  • the neurocognitive performance data of the patient pre- and post-DSR administration are shown in Table 2.
  • DSR treatment had a favorable effect upon cognitive performance, as measured by the employed test battery, with evident improvements in the domains of working memory, abstraction and mental flexibility. While at baseline the patient could not comprehend/perform the DST, TMT and WCST tasks, these tests were successfully completed post-DSR treatment (Table 2).
  • FIG. 1A A response to DSR treatment, consisting of an attenuation of the EDB pattern, was also registered in terms of the EEG parameters registered pre- and post-DSR administration ( FIG. 1A ).
  • short-term DSR treatment resulted in significantly improved quality of life, including reduction in psychopathology symptoms, improved motor symptomatology, improved cognitive performance, including improved working memory, abstraction and mental flexibility.
  • Rodent neuron cell cultures are treated with anti-NMDAR antibodies as described in Hughes E G et al., J Neurosci 2012 30(17):5866-75.
  • D-Serine for example at a concentration of 50-200 uM, or Glycine, at a concentration of 100-500 uM is added to some of the cultures, reversing receptor intracellular localization. The determination of receptors localization and other relevant measures is based on histological measurements.
  • Immunohistochemical methods will be applied to document (a) localization of NMDAR and NR1 and NR2 subunits; (b) loss of oligodendrocytes; (c) changes in astrocytes (S100beta) and microglia (cd11b), (d) expression of neurotrophic factors: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF); (e) markers of neurogenesis—doublecortin (17) and apoptosis—caspase3 (9). Quantification of histological measurements is based on images in several cortical subregions, striatum, globus pallidus, substantia nigra, hippocampus, and cerebellum.
  • BDNF brain derived neurotrophic factor
  • NGF nerve growth factor
  • CNTF ciliary neurotrophic factor
  • “about” refers to a quality wherein the means to satisfy a specific need is met, e.g., the size may be largely but not wholly that which is specified but it meets the specific need of cartilage repair at a site of cartilage repair.
  • “about” refers to being closely or approximate to, but not exactly. A small margin of error is present. This margin of error would not exceed plus or minus the same integer value. For instance, about 0.1 micrometers would mean no lower than 0 but no higher than 0.2.
  • the term “about” with regard to a reference value encompasses a deviation from the amount by no more than 5%, no more than 10% or no more than 20% either above or below the indicated value.
  • the invention provides, in various embodiments, all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.
  • elements are presented as lists, e.g. in Markush group format or the like, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

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US10668036B2 (en) 2017-11-22 2020-06-02 Concert Pharmaceuticals, Inc. Deuterated analogs of D-serine and uses thereof
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